Pharmacological therapy utilizing pure formulations of S(xe2x88x92) amlodipine results in effective theraputic results while avoiding toxicities and adverse effects of racemic amlodipine. The methods and compositions described include the enriched deuterated forms of amlodipine as well as the nonenriched form. Amlodipine and deuteroamlodipine have a chiral center at C4 in the dihydropyridine ring, and thus can exist as optical isomers. The isomers may be separated by various methods, for example selective crystallization and column chromatography. See for example T. Shibanuma, et al., Chem. Pharm. Bull., 28, 2809-2812 (1980). Alternatively, S(xe2x88x92) amlodipine may be prepared using optically active reactants, or by a combination of separation and chiral synthesis. Optical isomers of compounds are specified (+) or (xe2x88x92), indicating the direction the chiral center rotates a plane of polarized light.
Optically active amlodipine, amlodipine derivatives and salts and deuterated amlodipine or deuterated amlodipine derivatives and salts are designated herein using the IUPAC R-S convention, sometimes called the xe2x80x9csequence rule.xe2x80x9d A description of the R-S convention may be found, for example, in xe2x80x9cIntroduction to Organic Chemistryxe2x80x9d by A. Streitwieser, Jr. and C. Heathcock, (Macmillan Pub. Co., New York, 1976), pages 110-114.
Optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been thought to be a potent teratogen.
The active compound of the present invention is the S(xe2x88x92) isomer of the compound amlodipine and the s(xe2x88x92) isomer of deuterated amlodipine. Amlodipine is described in U.S. Pat. No. 4,572,909. Chemically, this compound is the S(xe2x88x92) isomer of amlodipine and is a long-acting calcium channel blocker.
Amlodipine is chemically described as (R.S.) 3-ethyl-5-1-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate. Its empirical formula is: C20H25ClN2O5. Also encompassed within the present invention are compositions and methods of using deuterated compounds which are related to amlodipine. In the structures given below, R represents either hydrogen or deuterium. In a-preferred embodiment, R1 represents either hydrogen or deuterium wherein one or more R1 is deuterium. The symbol xe2x80x9c*xe2x80x9d denotes the chiral carbon. 
The present commercial formulation of amlodipine contains the drug as the salt; amlodipine besylate. The term xe2x80x9camlodipinexe2x80x9d herein refers to amlodipine and its pharmaceutically suitable salts and esters including amlodipine besylate and deuterated amlodipine and its pharmaceutically acceptable salts and esters including deuterated amlodipine besylate. This isomer will hereinafter be referred to as S(xe2x88x92) amlodipine. The terms xe2x80x9cS(xe2x88x92) amlodipinexe2x80x9d and xe2x80x9cS(xe2x88x92) isomer of amlodipinexe2x80x9d as used herein includes substantially optically pure S(xe2x88x92) amlodipine as well as optically pure S(xe2x88x92) amlodipine.
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The (xe2x88x92) isomer has been reported to be more active than the (+) isomer. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:
Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (after-load) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal""s or variant) angina.
After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required.
Hemodynamics: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/xe2x88x922 mmHg).
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to-man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
In a double-blind, placebo-controlled clinical trial involving 118 patients with well compensated heart failure (NYHA Class II and Class III), treatment with amlodipine did not lead to worsened heart failure, based on measures of exercise tolerance, left ventricular ejection fraction and clinical symptomatology. Studies in patients with NYHA Class IV heart failure have not been performed and, in general, all calcium channel blockers should be used with caution in any patient with heart failure.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24 hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black and white patients.
The effectiveness of 5-10 mg/day of amlodipine in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (648 amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8 studies significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. Amlodipine 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).
In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, amlodipine therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p less than 0.01). Two of 23 amlodipine and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.
Amlodipine is presently administered and is available commercially only as the 1:1 racemic mixture. That is, it is available as a mixture of optical isomers, called enantiomers. As stated above, enantiomers are structurally identical compounds which differ only in that one isomer is a mirror image of the other and the mirror images cannot be superimposed. This phenomenon is known as chirality.
Dihydropyridine calcium channel blockers are also known as calcium antagonists. The concept of a. specific mechanism of pharmacologic action related to the antagonism of calcium movement in the process of excitation-contraction was suggested by Fleckenstein et. al. See Calcium Antagonism in Heart and Smooth Muscle:Experimental Facts and Therapeutic Prospects, New York, Wiley, 1983. (See also Swamy, V. and D. Triggle, Modern Pharmacology, 2nd. Ed., Craig and Stitzel, Eds., Little, Brown and Co., Boston, 1986, Chapt. 26, 373-380; and Triggle, D. J., and R. A. Janis, Ann. Rev. Pharm. and Tox. 27: 347-369, 1987). Many of the currently available calcium antagonists appear to antagonize the entry of calcium through voltage dependent channels in the plasma membrane of cells. The pharmacologic class of calcium antagonists consists of chemically diverse compounds. Given the structural heterogeneity of the class it is likely that the pharmacological action involves more than one site or mechanism of action.
Amlodipine is one of a series of dihydropyridine calcium antagonists. Its ability to block calcium channels in smooth muscle produces peripheral vasodilation resulting in decreases in both systolic and diastolic blood pressure in hypertensive animals and humans.
Cellular calcium flux is regulated by receptor-operated and voltage-dependent channels which are sensitive to inhibition by calcium entry blockers. The term calcium antagonist was introduced by Fleckenstein (1964,1967) when two drugs, prenylamine and verapamil, originally found as coronary dilators in the LANGENDORFF-experiment, were shown to mimic the cardiac effects of simple Ca++-withdrawal, diminishing Ca++-dependent high energy phosphate utilization, contractile force, and oxygen requirement of the beating heart without impairing the Na+-dependent action potential parameters. These effects were clearly distinguishable from b-receptor blockade and could promptly be neutralized by elevated Ca++, xcex2-adrenergic catecholamines, or cardiac glycosides, measures that restore the Ca++ supply to the contractile system. In the following years many Ca++-antagonists were introduced to therapy. Specific Ca++-antagonists interfere with the uptake of Ca++ into the myocardium and prevent myocardial necrotization arising from deleterious intracellular Ca++ overload. They act basically as specific inhibitors of the slow transsarcolemnal Ca++ influx but do not or only slightly affect the fast Na+ current that initiates normal myocardial excitation.
Calcium channels and the sites of action of drugs modifying channel function have been classified (Bean 1989, Porzig 1990, Tsien and Tsien 1990, Spedding and Paoletti 1992). Four main types of voltage dependent calcium channels are described: L type (for long lasting), T type (for transient), N type (for neuronal), and P type (for Purkinje cells). They differ not only by their function (Dolphin 1991) and localization in tissues and cells but also by their sensitivity to pharmacological agents (Ferrante and Triggle 1990, Dascal 1990) and by their specificity to radioligands. The widely distributed L type channels exist in isoforms (L1, 2, 3, 4) and consist of several subunits, known as xcex11, xcex12 xcex2, y, xcex4. They are sensitive to dihydropyridines, phenylalkylamines or benzothiazepines, but insensitive to xcfx89-conotoxin and xcfx89-agatoxin. The T type channels are located mainly in the cardiac sinoatrial node and have different electrophysiological characteristics from L type channels. N- and P-type calcium channels blockers occur in neuronal cells and are involved in neurotransmitter release (Bertolino and Llinas 1992, Mintz et al 1992). Up to now, there are no highly selective blockers of T-, N-, and P-channeis with potential therapeutic applications.
The racemic mixture of amlodipine is presently used primarily as an antihypertensive agent, and it is generally taken orally as a once-daily therapy. Pharmacologic management of hypertension is generally directed to the normalization of altered hemodynamic parameters, and many drugs and drug classes, either as monotherapy or in combination treatment, can reduce and control elevated blood pressure.
Furthermore, the racemic mixture of amlodipine is useful in treating other disorders such as angina pectoris. Angina pectoris is a clinical syndrome reflecting myocardial ischemia. A condition where cardiac work or myocardial oxygen demand exceeds the ability of the coronary arterial vascular system to supply oxygen results in myocardial ischemia, which may cause either a painful angina attack or an angina attack that is not accompanied by pain (silent ischemia). Under extreme circumstances, the lack of oxygen may cause a myocardial infarction or cardiac arrhythmias. The treatment of angina is directed to the underlying disease, usually atherosclerosis, or to drugs which either reduce myocardial oxygen demand or improve oxygen supply. Calcium antagonists such as amlodipine have been particularly useful in treating vasospastic angina, the angina of effort, and the unstable angina, due to the effect of the calcium channel antagonist on cardiac and vascular smooth muscle.
Amlodipine may be useful in the treatment of cerebral ischemia. Cerebral ischemia, often the result of atherosclerotic disease or hypertension, results from insufficient cerebral circulation. Under normal circumstances, an extensive collateral circulation ensures adequate blood flow. However, cerebral ischemia may result from either an intra or extracranial interruption of arterial blood flow caused by atherosclerosis or arterial vasoconstriction. If interruption is transient, the cause is usually arterial vasoconstriction and a calcium antagonist may be of therapeutic value. If the ischemia lasts for a more extended period, it is usually caused by carotid or cerebral atherosclerosis that may be accompanied by a vasospecific condition that can be treated with a vasodilating calcium antagonist.
Because of its activity as a calcium channel antagonist, amlodipine may also be useful in treating cardiac arrhythmias. Cardiac arrhythmias represent a broad, complex group of electrophysiologic disorders that effects the mechanical properties of the heart and vasculature, altering normal cardiac rhythm, function and output. Normal cardiac rhythm originates as a calcium dependent action potential within the sinoatrial node, propagates through the atria and passes as a calcium dependent potential through the atrioventricular node and along the purkinje fibers into the ventricles of the heart. Adequate automaticity and conduction are necessary elements of normal functional heart beat. Calcium antagonists may be of value in conditions where calcium-related changes in membrane potential and conduction alter normal rhythm and in cases of ischemia-induced cardiac arrhythmias.
Amlodipine may be useful to treat cardiac hypertrophy. Cardiac hypertrophy can result from excessive workload either due to an obstruction to outflow, termed systolic overload, or to excessive volumes presented to the heart in diastole, termed diastolic overload. Systolic overload results in concentric ventricular hypertrophy, in which there is an increased thickness in the walls of the heart not associated with increased volume. Diastolic overload causes dilation and hypertrophy with an increased blood volume. An inadequate cardiac output results from the heart""s failure in systolic or diastolic overload. Calcium channel antagonists dilate peripheral capacitance blood vessels and thereby reduce the amount of blood returning to the heart and the risk for diastolic overload. Calcium antagonists also dilate peripheral resistance blood vessels, thereby reducing blood pressure (cardiac afterload) and the risk for systolic overload.
Myocardial infarction may be precipitated by coronary artery vasospasm or acute coronary thrombosis. Calcium channel antagonists may find utility in the management of myocardial infarction patients due to xe2x80x9cdirectxe2x80x9d anti-ischemic effects or due to their effects on coronary artery vasospasm, blood pressure or other cardiac or vascular functions.
Amlodipine may be used to treat congestive heart failure. Congestive heart failure can be caused by hypertension, cardiomyopathy, coronary artery disease or valvular heart disease. Congestive failure results in poor cardiac output and elevated left-ventricular diastolic pressure, leading to dyspnea, fatigue, peripheral edema, and coughing. The ability of some calcium antagonists to lower arterial blood pressure by dilating peripheral arteries without having a significant inotropic effect may increase their use in treating congestive heart failure.
Amlodipine may be of use in treating migraine. Classic migraine typically begins with visual auras followed by severe headaches, often accompanied by nausea and vomiting. Common migraine has similar symptoms without the preceding visual aura. The causes of migraine have been studied intensely, and are still a matter of debate. The most generally accepted cause is an initial cerebral vasoconstriction, followed by a cerebral vasodilatation. Calcium channel antagonists have been used for migraine prophylaxis since they can inhibit the initial vasoconstriction.
Amlodipine may also be useful for treating Raynaud""s phenomenon, which is characterized by vascular spasm of the extremities. These vasospasms can be caused by cold or stress. A pallor or cyanosis is usually present due to severe constriction of the digital arteries. The phenomenon is often seen as a secondary disorder with arterial diseases or connective tissue diseases such as scleroderma, arthritis or lupus erythematosus. Calcium channel antagonists have been shown to be effective in treating Raynaud""s phenomenon.
Amlodipine may be useful in the treatment of asthma and bronchospasm. Symptoms of asthma-coughing, wheezing, and dyspnea-are caused by constriction of tracheobronchial smooth muscle. Asthma attacks can be triggered by antigenic stimuli (pollen, dust) or non-antigenic stimuli (exercise, pollution, infection). The response to these stimuli lead to secretions of chemical mediators that cause smooth muscle contraction. Calcium channel antagonists can cause relaxation of the bronchial smooth muscles and thereby relieve or prevent asthma attacks.
The racemic mixture of amlodipine may be useful to treat renal impairment and acute renal failure. Renal impairment and acute renal failure are clinical conditions of diverse etiology, which are associated with an increasing azotemia or urea nitrogen in the blood, and often an oliguria or a diminished volume of urine in relation to fluid intake. The pathophysiology may originate prerenally, manifest as inadequate renal perfusion, due to extracellular fluid volume depletion or cardiac failure. The most common cause of intrinsic renal failure is prolonged renal ischemia. Postrenal azotemia may be associated with obstruction or renal glomerular and tubular dysfunction. Laboratory findings in patients with renal failure often disclose progressive azotemia, acidosis, hyperkalemia, and hyponatremia. Factors aggravating kidney impairment or failure must be specifically treated, including heart failure, obstruction and the like. Moderate or severe hypertension has a deleterious effect on renal function, and management of the hypertension with a variety of drugs including calcium channel antagonists may be useful therapy.
In addition, the racemic mixture of amlodipine could be useful in the treatment of cognitive disorders. Cognitive disorders include but are not limited to dementia and age-associated memory impairment.
Calcium antagonists such as amlodipine may also be used for the treatment of ocular (retinal) ischemia, that often is the result of local vasoconstriction.
Many calcium channel antagonists cause significant adverse effects. These adverse effects include but are not limited to tachycardia, orthostatic hypotension, fluid retention and insulin resistance. The administration of the racemic mixture of amlodipine to a human has been found to cause still other adverse effects. These adverse effects include but are not limited to headache and edema, dizziness, flushing, palpitation, fatigue, nausea, abdominal pain and somnolence.
The methods and compositions of the present invention utilize the discovery that the optically pure S(xe2x88x92) isomer of amlodipine is an effective antihypertensive agent for both systolic and diastolic hypertension, particularly in mild to moderate disease and angina, which avoids the adverse effects including but not limited to headache and edema, dizziness, flushing, palpitation, fatigue, nausea, abdominal pain and somnolence which are associated with the administration of the racemic mixture of amlodipine. It has also been discovered that these novel compositions of matter containing optically pure S(xe2x88x92) amlodipine are useful in treating other conditions as may be related to the activity of S(xe2x88x92) amlodipine as a calcium channel antagonist, including but not limited to cerebral ischemia, cerebral disorders, arrhythmias, cardiac hypertrophy, heart failure, coronary vasospasm, myocardial infarction, renal impairment, viral infection, thrombosis, atherosclerosis, peripheral vascular disease, migraine headache, restenosis following vascular surgery or injury and acute renal failure while avoiding the above-described adverse effects associated with the administration of the racemic mixture of amlodipine. The present invention also includes methods for treating the above-described conditions in a human while avoiding the adverse effects that are associated with the racemic mixture of amlodipine by administering the S(xe2x88x92) isomer of amlodipine to said human.
The present invention relates to a method of treating hypertension in an individual, comprising administering to the individual a therapeutically effective amount of the optically pure S(xe2x88x92) enantiomer of amlodipine which has calcium channel blocking activity. The optically pure S(xe2x88x92) enantiomer is substantially free of the R(+) enantiomer which lacks or has a lower level of such activity. The present method is useful in treating hypertension while reducing or avoiding undesirable adverse effects, such as headache and edema, dizziness, flushing, palpitation, fatigue, nausea, abdominal pain and somnolence which are often associated with administration of a racemic mixture of amlodipine. In these applications, it is important to have an calcium channel blocking composition which minimize these side effects. A composition containing the optically pure S(xe2x88x92) isomer of amlodipine having calcium channel blocking activity is particularly useful for this application because the S(xe2x88x92) isomer exhibits both of these desired characteristics.
The present method provides a safe, highly effective method for treating severe hypertension while reducing undesirable adverse effects associated with anti-hypertensive drugs, including the racemic mixture of amlodipine.